Epigenetics
Epigenetics Overview Over the years, the definition of epigenetics has narrowed from a broad understanding to the science of determining which expressed or inhibited genes result in a unique phenotype (1). While every cell in an individual’s body may posses exactly the same genetic matter, not every cell does the same function; this is because of unique gene expression within every cell. An epigenetic system is described as being heritable, reversible, and self-perpetuating; gene expression within all cells should maintain these three properties (2). The basis of epigenetics involves understanding how a non-genetic cellular memory system is able to track and record developmental and environmental cues the cell senses (2). However, a distinct aspect of epigenetic studies takes into account that these epigenetic changes are altered by factors other than a cell’s DNA content. In other words, epigenetic modifications occur separately from the pre-programmed nature of the cell, and are due to outside signals directed at the cell and its nucleus (1; 4). Epigenetic Modification of Genes It is widely believed that there are three systems involved in epigenetic silencing of genes: RNA-associated silencing, histone modification, and DNA methylation. RNA-associated Silencing Genes can be silenced by RNA; more commonly, genes are silenced by small RNAs. Specific gene sequence regulation can be triggered by double-stranded RNA, RNA interference, or subclasses of small interfering RNAs. RNA-associated silencing may affect gene expression by triggering histone modifications and DNA methylation; it may also result in the formation of heterochromatin, and therefore, inactivated genes (1). Histone Modification Histone proteins, also known as the spools in which DNA is wound around, determine how chromatin is arranged within a chromosome. Unwound, loose chromatin is considered active, and can be transcribed; wound, dense chromatin is considered inactive, and cannot be transcribed; the latter of these two is also known as heterochromatin. Chromatin can be modified by acetylation (and deacetylation) or methylation, depending on whether the chromatin is dense or loose. Histone protein modifications are regulated by epigenetic signals and markers sent to and placed on DNA, resulting in the subsequent chromatin arrangement (1). DNA Methylation DNA methylation is a chemical process resulting in the addition of a methyl-group onto a nucleotide of DNA. Adding a methyl-group onto DNA alters the structure and therefore appearance of the DNA; this results in new and unique interactions between the DNA and the cell’s nucleus. Methylation is a process that occurs on guanine and cytosine nucleobases, but in mammalian cells is more common on the latter of the two (2; 3). Excessive methylation, also known as hypermethylation, can lead to epigenetic abnormalities. Cancer is considered the first epigenetic disease discovered, and can be caused by extreme modifications within a DNA sequence. For example, hypermethylation near promoter regions within DNA can result in the inhibition of tumor suppressor genes, resulting in cancerous growth (2). How an Epigenetic Pathway is Established Three distinct categories of signals come together to establish a heritable epigenetic state. An epigenator is established from an environmental cue outside the cell. This epigenator is converted into an intracellular signal that then activates the epigenetic initiator within the cell. An epigenator is only necessary to activate the initiator, and serves no other purpose (3). An epigenetic initiator translates the intracellular signal of the epigenator into a specific location on a chromosome. This precise location will be the site of new, epigenetically-modified chromatin. Through positive feed-back mechanisms, the epigenetic initiator will self-renew and self-enforce itself to establish this location and activate an epigenetic maintainer ''(3). An ''epigenetic maintainer is a mechanism of pathways that sustains the epigenetic chromatin state, but is not adequate enough to initiate the signal itself. These pathways may involve RNA-associated silencing, histone modification, or DNA methylation. An epigenetic maintainer can serve its purpose at any chromosomal site to which it is recruited (3). References 1) Dupont C, Armant DR, Brenner CA. Epigenetics: Definition, Mechanisms and Clinical Perspective. Semin Reprod Med. September 2009; 27(5): 351-357. doi: 10.1055/s-0029-1237423 2) Riddihough G, Zahn LM. What is Epigenetics? Science. October 2010; 330(6004): 611. doi: 10.1126/science.330.6004.611 3) Berger SL, Kouzarides T, Shiekhattar R, et. al. An operational definition of epigenetics. Genes & Dev. 2009; 23: 781-783. doi: 10.1101/gad.1787609 4) Simmons D. Epigenetic Influences and Disease. Nature Education. 2008; 1(1): 6. Article Link: http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895